Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype.

Kinga Hadzsiev,Bela Melegh,Gyorgy Kosztolanyi,Renata Szalai,Katalin Komlosi,Andras Szabo,Etelka Postyeni,Balazs Duga,Marta Czako,Titanilla Szabo

doi:10.1186/s13039-016-0231-2

Abstract

BackgroundKleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1.Case presentationWe describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom – abnormal antiepileptic drug metabolic response – could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large – 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911.ConclusionsThis is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.

Highlights

Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia
This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism
We made a comparison between the symptoms of our patients and of patients with 9q subtelomeric deletions presented by Kleefstra (Table 1) [8]

Summary

Introduction

Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. In the phenotype of the syndrome developmental delay/ intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carp mouth with macroglossia - and childhood hypotonia are present in all Hadzsiev et al Molecular Cytogenetics (2016) 9:22 the minimum critical region is 1.2 Mb and includes 14 genes on the long arm of chromosome 9, which could be responsible for the 9q subtelomeric deletion syndrome [5]. There are some patients showing the core phenotypic features, but with phenotypic heterogeneity of KS in whom Kleefstra et al identified de novo mutations in four epigenetic regulator genes, namely in MBD5, MLL3, SMARCB1 and NR1I3 [7]

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